IDENTIFICATION OF A MUTATION NEAR A FUNCTIONAL SITE OF THE BETA-CARDIAC MYOSIN HEAVY-CHAIN GENE IN A FAMILY WITH HYPERTROPHIC CARDIOMYOPATHY

Several mutations within the gene coding for the cardiac beta myosin h eavy chain (designed MYH7) have been shown to be responsible for Famil ial Hypertrophic Cardiomyopathy (FHC) in several families, and evidenc e of genetic heterogeneity has been reported. To investigate the MYH7 gene as the cause of the disease in a small family with FHC, inheritan ce of the disease and chromosome 14 q11-q12 markers haplotype were stu died, exons coding for the head domain of the cardiac beta myosin heav y chain (beta MHC) were analysed for mutations by MDE gel electrophore sis, and sequenced. We report a mutation within exon eight of the MYH7 gene at a very conserved amino acid at position 232, which results in the conversion of an asparagine to serine. This residue Asn-232 is lo cated in a MHC area that has been recently identified as a critical si te for ATPase activity. According to recent results on the three-dimen sional structure of the myosin head or subfragment-1 (S1), Asn-232 is located in an alpha-helix which forms part of the nucleotide binding p ocket. Although this mutation affects an active site, it seems to be a ssociated with a favourable prognosis and a weak penetrance in this fa mily.